Sterility testing product filtration

Product Name) can be tested for sterility by membrane filtration with 3 X 300 rinsing fluid A after incubation of 14 days and more than one week. 

Filter media are not repetitive-use items, and although used for more than one lot in production, the media are usually discarded after some predetermined number of uses or time. Therefore, it is impossible to test every filter medium individually, since the challenge test is a destructive test. The nondestructive tests, therefore, require a high degree of correlation with a retention test. When such correlated tests are established and controls maintained, filtration users can depend on filtration to produce a sterile parenteral product. 

The USP describes two general methods for conducting the test the direct transfer, or direct inoculation, method and the membrane filtration method. As the name indicates, the direct inoculation method involves the aseptic transfer of a sample of test product solution into the sterility test growth medium. To use this method, it must first be demonstrated that the product solution itself does not inhibit the growth of typical indicator microorganisms specified in the USP method. It should be self-evident why it is important to perform testing to negate the chance of product inhibition of possible microbial contaminants, as this is the purpose of the sterility test. The direct inoculation method, while not theoretically complex, requires the utmost technical precision and aseptic manipulation techniques for proper execution. As a consequence of the repetitive motions involved, it is prone to human error. 

Finally, it is recognized that for short-lived radiopharmaceuticals, the long incubation time of the culture media (7 days for the membrane filtration technique, 14 days for direct inoculation) means the result of the sterility test cannot be available before the product is used. In these situations, the test constitutes a control of production techniques and will give valuable information about their suitability. 

The prime purpose of sterile filtration is to produce a sterile effluent that has not been altered as a result of the process of sterilization. Within these considerations. validation must address the performance of both the filler media and the whole filtration unit including housings, seals, connections, etc., versus its practical application. As with any other sterilization process, the continued effectiveness of sterile filmuion cannot be assumed without confirmation from routine monitoring end-product sterility testing (or testing for nonsteriiity) is unsuited for this purpose. 

During batch preparation sterility testing can be performed on randomly selected preparations either by direct inoculation or by the filtration method. During extemporaneous preparation dummy solutions should be prepared and sterility tests performed with rapid detection methods such as the bioluminescence test (see Sect. 19.6.5) or the colorimetric detection of CO2 production in culture bottles although commonly used for blood cultures this last method was shown to be adequate for sterility testing of multicomponent admixtures [68]. 

Pharmaceuticals for injection must be presented in a sterile form. Sterility may be achieved by filtration through 0.22 pm filters under aseptic conditions, or by steam, dry heat, radiation or gas sterilisation methods, which may be applied to packaged products. Irrespective of the method, the process must be validated and monitored to assure its effectiveness. As discussed in Chapter 2, this is an example of a process that cannot be assured by verification testing because of its destructive nature. 

Perform a pressure hold test with the sterilized filter. Perform the filtration of the product to be sterile filtered using normal production conditions. After the filtration step, the filter should be tested again with the bubble point test. 

Filters are used for clarification, removal of small molecules, exchange of buffers, and concentration of product, as well as sterilization and virus removal. A recent review of validation of filtration describes the critical validation issues [29], Filter compatibility is tested with process conditions to avoid nonspecific binding of product to the filter or addition of extractables to the process stream. Extractables are defined and limits established based on final product safety studies. Special considerations apply for sterilizing filters and those that are designed for virus removal. These filters are single use, however, which simplifies the validation effort. 

Unlike sterilizing and virus removal filters, tangential flow filtration (TFF) filters are often reused. Flow and integrity tests are necessary to ensure the filter remains the same after usage and cleaning. Consistency of filtrate and retentate streams is validated using relevant validated assays that are specific for each process and product. 

TR 11 Sterilization of Parenterals by Gamma Irradiation, 1988 TR 13 Fundamentals of an Environmental Monitoring Program, 2001 TR 22 Process Simulation Testing for Aseptically Filled Products, 1996 TR 26 Sterilizing Filtration of Liquids, 1998... 

Sterile filter compatibility testing. It should be demonstrated that filters of the same surface area as for commercial batches are compatible with the formulation being filtered [16]. The filter should not induce significant degradation of the active product or leach out undesirable substances. The retention of active material inside the filter, in other words the loss on filtration, should be quantified and assessed statistically. 

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